Severe Gross Hematuria Associated with Antithrombotic Drugs: Management and Impact on Prescription Thereafter

Research Article

Thromb Haemost Res. 2023; 7(2): 1092.

Severe Gross Hematuria Associated with Antithrombotic Drugs: Management and Impact on Prescription Thereafter

Bouget J1,2*; Balusson F3; Roy PM4; Viglino D5; Pavageau L6; Lacut K7†; Khene ZE8; Scailteux LM3; Oger E3

11Univ Rennes, CHU Rennes, EA 7449 [Pharmacoepidemiology and Health Services Research] REPERES, F 35043 Rennes, France

2Emergency Department, Rennes University Hospital, F 35033 Rennes, France

3Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Rennes, France

4Emergency Department, Angers University Hospital, Institut MITOVASC, Université d’Angers, F 49033 Angers, France

5Emergency Department, Grenoble-Alpes University Hospital, F 38043 Grenoble, France

6Emergency Department, University hospital, F 44093 Nantes, France

7CIC 1412, Université de Bretagne Loire, Université de Brest, INSERM CIC 1412, CHRU de Brest, F 29200 Brest, France; †who passed away in April 2021

8Department of Urology, Rennes University Hospital, F 35033 Rennes, France

*Corresponding author: Bouget Jacques University of Rennes 1, Campus Santé Villejean, Bâtiment 6 RDC, F 35043 Rennes, France. Tel: +33223234732 Email: jacques.bouget@univ-rennes1.fr

Received: August 04, 2023 Accepted: September 02, 2023 Published: September 09, 2023

Abstract

Anfibatide is a synthetic antiplatelet thrombolysin derived from snake venom and is proposed to treat ischemic stroke and cerebral ischemia-reperfusion injury. Current standard treatments for ischemic stroke include the administration of rt-PA, a thrombolytic agent, or endovascular removal of thrombi. However, the post-treatments are often associated with the occlusion of vessels due to a lack of antiplatelet and unrecovered vessel injury. Anfibatide, as a GPIba antagonist that interrupts the initiation of platelet aggregation caused by GPIba-vWF binding, becomes a potential novel candidate for treating ischemic stroke due to its antiplatelet and antithrombosis effects. Key findings show that Anfibatide can significantly reduce microthrombus formation in cerebral vessels and reduce neuron apoptosis due to the release of pro-inflammatory mediators caused by ischemia or Ischemia-Reperfusion (I/R) injury. Significant improvement in neurological scores and reversal of brain structure alterations are observed in the Anfibatide-treated ischemic animal models. To facilitate the clinical development of Anfibatide, this paper aims to summarize the completed preclinical studies and the Phase I clinical trial results of anfibatide to evaluate the risks and therapeutic potentials of Anfibatide in ischemic patients.

Keywords: Anfibatide; Ischemic stroke; Cerebral ischemia-reperfusion injury; Antiplatelet; GPIba-vWF binding; Antithrombosis

Abbreviation: rt-PA: Recombinant Tissue Plasminogen Activator; MT: Mechanical Thrombectomy; DALY: Disability-Adjusted Life Years; GP: Glycoprotein; NS: Normal Saline; FCA: Freund’s Complete Adjuvant; ICH: Intracerebral Hemorrhage; Β-TG: Β-thromboglobulin; H&E staining: Hematoxylin and Eosin staining; SOD: Serum superoxide dismutase; GSH-Px: Serum Gutathione Peroxidase; MDA: Malonaldehyde; LDH: Lactate Dehydrogenase; NO: Nitrogen Oxides; I/R injury: Ischemia-Reperfusion Injury; EI: Edaravone-Injection; CRI: Constant Rate Infusion; PRP: Platelet-Rich Plasma; PT: Prothrombin Time; TT: Thrombin Time; aPTT: Activated Thromboplastin Time; INR: International Normalized Ratio

Introduction

Antithrombotic agents are the most commonly prescribed medications for older adults in the world. In this population, warfarin and antiplatelet agents represented respectively the first and the third medications leading to emergency hospitalizations for adverse effects [1]. Bleeding represent the most well-known and feared complication of antithrombotic agents. Most of clinical trials and observational studies have focused on Intracranial Hemorrhage (ICH) and Gastrointestinal (GI) bleeding associated with oral anticoagulants or antiplatelet agents [1-5]. Studies reporting on hematuria appear scarcer.

In a large cohort study, Wallis et al reported that use of antithrombotic agents was associated with a significant increased rate of hematuria-related complications compared to patients not exposed, with an incidence rate ratio of 10 [6]. Rate of gross hematuria among patients referred to emergency department while receiving any type of antithrombotic agent ranged from 3.9 to 5.7% [7,8]. This rate was higher in patients receiving oral anticoagulants, from 3% up to 24% depending on the methodology and the definition of bleeding severity used [3,9-13]. In patients prescribed with antiplatelet agents it appeared lower than that in patients with oral anticoagulants [14,15]. Hematuria is considered less life-threatening bleeding than ICH or GI bleeding. Hematuria is common in Emergency Department (ED) and involves diagnostic evaluation and therapeutic management even if its etiology is not always found [16,17]. In addition, to our knowledge, decision about antithrombotic treatment after severe hematuria has never been reported. Our objectives were to describe the management of patients referred for severe gross hematuria while receiving oral antithromboticagents, and to assess factors associated with antithrombotic prescription thereafter.

Methods

Design, Data Sources and Study Population

The SACHA (Surveillance des ACcidents Hémorragiques sous Antithrombotiques) study is a French prospective multicentric population-based cohort study on the incidence and outcome of major bleeding in patients treated with antithrombotic agents. The study design has been previously reported [18]. The SACHA study included a total of 6484 patients with major bleeding events during a 3-year period. For the current analysis, only patients treated with oral antithrombotic agents admitted to EDs for severe gross hematuria were studied.

From emergency departments within five well-defined areas around five large French cities (Angers, Brest, Grenoble, Nantes and Rennes), demographic data (age, gender), clinical data (co-morbid conditions, antithrombotic drug class with presumed indication and time since initiation, systolic blood pressure), as well as biological data (hemoglobin and creatinine level), therapeutic management such as red blood transfusion, platelet transfusion, plasma transfusion, vitamin K, protamin sulfate, Prothrombin Complex Concentrate (PCC) and FEIBA® (anti-inhibitor coagulant complex), and hospital data (endoscopic or surgical procedures, ward type (medical or surgical), Intensive Care Unit (ICU) stay, Length Of Stay (LOS), and case fatality) were collected. A modified Charlson index was calculated for each patient [19]. The CHA2DS2VaASc score was calculated for patient receiving oral anticoagulants [20]. Modification of Diet in Renal Disease (MDRD) was also calculated [21]. In each emergency department, the local referent medical doctor validated the inclusion, and specifically the bleeding severity defined as having at least one of the following criteria [22]: unstable hemodynamics (systolic arterial pressure <90 mmHg or mean arterial pressure <65 mm Hg) or hemorrhagic shock, uncontrollable bleeding, need for transfusion or hemostatic procedure (embolization, surgery). This is slightly different from the International Society on Thrombosis and Haemostasis (ISTH) classification of major bleeding events, because no information was available on hemoglobin levels before emergency department referral [23]. Bleeding lasted more than 12 hours despite bladder washing was also defined as severe hematuria.

The clinical database was linked to the French Health Insurance Database (SNIIRAM) using common key variables (date of birth (month, year), gender, date of hospital entry and discharge, type of antithrombotic therapy, and care facility involved) [18]. The SNIIRAM contains anonymous individual data on all reimbursements for health expenditure, including drugs (of note, the database does not provide the medical indication for each drug prescription); hospital discharge diagnoses (ICD-10 code) as well as details on medical acts. We identified pre-existing urologic diseases (before hematuria) and extracted the discharge diagnoses (main and secondary, focusing on urologic disease) as well as the medical procedures (endoscopy, surgery) coded for the hospitalization related to the index hematuria.

For this analysis, we considered only patients (i) referred for severe gross hematuria without any other concurrent bleeding between January 1, 2013 and December 31, 2015, retaining the first occurrence as index hematuria, (ii) with a stable oral antithrombotic regimen before referral (i.e., without any change in therapeutic class or posology of antithrombotic agents, within 3 months prior to hematuria). Of note, hematuria during hospitalization whereas patient was referred for another reason and intentional overdose of antithrombotic agents were excluded. All oral antithrombotic agents were included in the study: vitamin K antagonist, direct oral anticoagulants, antiplatelets agents (mono or dual therapy) and any combinations of these drugs.

The study received regulatory approval (Commission Nationale de l’Informatique et des Libertés “CNIL”, #DR-2013-488 with subsequent substantial changes #DR-2016-489); ClinicalTrials.gov identifier: NCT02886533.

Outcomes

We first considered hospital outcome, focusing on ward type (medical or surgical), Intensive Care Unit (ICU) stay, Length Of Stay (LOS), and case fatality.

After hospital discharge, antithrombotic prescription was categorized into 3 classes according to SNIIRAM data for drug delivery in a 3-month follow-up period: no change, or class change when compared to the regimen before (drug delivery in a 3-month period before referral for severe gross hematuria), or discontinuation (no antithrombotic drug delivery in the following 3 months).

During a 3-month follow-up period after hospital discharge for severe gross hematuria, we retrieved SNIIRAM data on the occurrence of hospitalization for bleeding or ischemic events as coded in main discharge diagnosis (ICD-10). No inform and signed consent was needed for the basic survey.

Statistical Analysis

Statistical analysis was performed from July 1 to October 31, 2022.

Clinical characteristics were described according to gender, whereas management and outcomes were described according to the type of antithrombotic drugs - Antiplatelet monotherapy or dual therapy, Vitamin K Antagonist (VKA) or Direct oral anticoagulant (DOAC)-. Descriptive statistics were frequency (percentage) for categorical variables, mean ± Standard Deviation for continuous variables with a gaussian distribution and median [first and third quartiles] otherwise. Comparisons across gender or across the type of antithrombotic drugs used chi-square test of Fisher exact test for categorical variables, Student t-test or analysis of variance for continuous variables with a gaussian distribution and Kruskal-Wallis test otherwise.

To estimate association between clinical predictors and antithrombotic prescription after hospital discharge (categorized as: no change, or class change when compared to the regimen before, or discontinuation, i.e. no antithrombotic drug delivery in the following 3 months), we ran a multivariable multinomial logistic regression model (generalized logit link) using “no change” as the reference category.

All statistical tests were two-tailed and P-values <0.05 were considered significant. Statistical analyses were performed using SAS software 9.4 (SAS Institute, Cary, N.C., USA).

Results

Clinical Characteristics

Over the study period, 400 patients referred for severe gross hematuria while receiving antithrombotic drugs were included. Considering stable antithrombotic regimen over 3 months before hematuria and no other concurrent bleeding 300 patients remained eligible. Clinical characteristics are reported in Table 1. There were 260 (87%) males, and 40 (13%) females; mean age was 78.8±10.1 years. Only 36 patients (12%) had a recent (within 3 months) history of hematuria (non-severe by design). The three most frequent comorbidities were arterial hypertension (60.3%), malignant disease (35.7%) and coronary artery disease (33.7%). Charlson’s comorbidity index was low (index <2 for 67.3% of patients).